Oxytrifluoromethylation of multiple bonds using copper catalyst under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2012.07.134

Oxytrifluoromethylation reaction of styrene derivatives and alkynes with external and internal oxygen nucleophiles, catalyzed by copper (I) salts under mild conditions, was developed. Direct formation of a β- trifluoromethylstyrene derivative from a styrene derivative was also achieved by the reaction in the presence of a Bronsted acid. Further transformation of the oxytrifluoromethylated products was conducted to demonstrate their utility. 2012 Elsevier Ltd. All rights reserved.

Full text of DOI:10.1016/j.tetlet.2012.07.134

Tetrahedron Letters 53 (2012) 5503–5506
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Oxytrifluoromethylation of multiple bonds using copper catalyst under
mild conditions
Hiromichi Egami a,b, Ryo Shimizu a,c, Mikiko Sodeoka a,b,c,
⇑
a RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
b Sodeoka Live Cell Chemistry Project, ERATO, Japan Science and Technology Agency, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
c Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama 338-8570, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Oxytrifluoromethylation reaction of styrene derivatives and alkynes with external and internal oxygen
nucleophiles, catalyzed by copper (I) salts under mild conditions, was developed. Direct formation of a
b-trifluoromethylstyrene derivative from a styrene derivative was also achieved by the reaction in the
presence of a Brønsted acid. Further transformation of the oxytrifluoromethylated products was con-
ducted to demonstrate their utility.
Received 19 July 2012
Revised 24 July 2012
Accepted 30 July 2012
Available online 5 August 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Trifluoromethylation
Copper
Olefin
Alkyne
Togni reagent
Fluorine chemistry has played an important role in pharmaceu-
tical chemistry, agrochemistry, and materials science for a long
time, and many types of fluorination reactions have been re-
ported.1,2 The trifluoromethyl group has attracted increasing atten-
tion because of its unique properties, which include metabolic
stability, lipophilicity, and hydrophobicity, and great efforts have
been devoted to developing reactions for its introduction into or-
ganic molecules.3 Recent successes include easier formation of
ping of the cationic intermediate with various oxygen nucleophiles
should give useful functionalized trifluoromethylated molecules
(Scheme 1). In this Letter, we describe the copper-catalyzed oxytri-
fluoromethylation of styrene derivatives and alkynes under mild
conditions.9,10 We also report further transformations of the oxy-
trifluoromethylated products, in order to demonstrate the utility
of this reaction.
C
sp2–CF3 bonds by using copper- or palladium-catalyzed cross-
coupling reactions.4 On the other hand, Csp3–CF3 bonds have
mainly been constructed via a carbonyl group, using a variety
of protocols.3,5
A noteworthy recent development has been
the deprotonative trifluoromethylation of simple C@C bonds.6,7
Nevertheless, new synthetic methods are still needed to achieve
C–CF3 bond formation, especially Csp3–CF3 bonds, in a wider range
of molecular contexts.
We recently reported the copper-catalyzed trifluoromethyla-
tion of allylsilanes using Togni reagent 18 under mild conditions
(Eq. 1).7 During this study, we found that methoxytrifluoromethy-
lation products, such as compound A,7 were generated from elec-
tron-rich
a-trimethylsilylmethyl-styrene derivatives and we
proposed that the reaction of 2-substituted allylsilanes proceeds
via a cationic intermediate.7 This mechanistic insight prompted
us to examine oxytrifluoromethylation reactions of olefins. Trap-
⇑
Corresponding author. Tel.: +81 48 467 9373; fax: +81 48 462 4666.
E-mail address: sodeoka@riken.jp (M. Sodeoka).
Scheme 1. Proposed mechanism of oxytrifluoromethylation.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.134

5504
H. Egami et al. / Tetrahedron Letters 53 (2012) 5503–5506
of substrates bearing an oxygen atom on a phenyl ring proceeded
smoothly to give the corresponding products 4b–4g in high yields.
It is noteworthy that this reaction was easy to scale up (4b). The
TBS group and aryl bromide were tolerant of the conditions em-
ployed, and non-protected phenols could be used in this reaction.
In addition, N-protected aniline derivatives gave the desired com-
pounds 4h and 4i in 94% and 93% yields, respectively. Although the
reaction rates of 2j and 2k bearing no heteroatom on the phenyl
ring were slower, the products 4g and 4k were obtained in good
yields.11 It should be noted that the oxytrifluoromethylation of
heteroaromatic compounds was achieved without difficulty (4l–
4o), and regioselective oxytrifluoromethylation of dienes was also
successful under the optimal conditions. The 1,4-adduct 4p was
selectively produced from trans-1-phenylbutadiene 2p in 91%
yield, while the 1,2-adduct 4q was produced from 1,1-diphenylbu-
tadiene 2q in 97% yield.
In order to demonstrate the utility of the oxytrifluoromethylat-
ed compounds, further transformations were examined (Scheme 2).
Hydrolysis of the 2-iodobenzoate proceeded smoothly under usual
conditions in 95% yield. After protection of the alcohol with a TIPS
group, ruthenium-catalyzed oxidative cleavage of the phenyl ring
afforded the carboxylic acid, which was treated with trimethylsi-
lyldiazomethane to give methyl ester 5 in 87%. Ozonolysis of 4q
gave aldehyde 6 in high yield.
ð1Þ
First, we applied our CuI–MeOH conditions to 4-methoxysty-
rene (2a). As we expected, methoxytrifluoromethylation pro-
ceeded smoothly at 40 °C to give 3a in 93% yield (Eq. 2).
Ethoxytrifluoromethylation and isopropyloxytrifluoromethylation
also proceeded without difficulty to give 3b and 3c, although the
efficiency of these reactions depended on the steric bulkiness of
the alcohol nucleophile. Interestingly, the 2-iodobenzoate adduct
(4a) was isolated in 6%, 9%, and 28% yields from the reactions in
MeOH, EtOH, and i-PrOH, respectively. Since the acyloxy com-
pound should be easily convertible to the hydroxyl derivative, this
would be an attractive reaction, if the acyloxy compound is the
major product.
In the course of examination of reaction conditions for the tri-
fluoromethylation, we also found a dramatic effect of Brønsted acid
on the product. Remarkably, the Heck-type product 7a was directly
obtained in 90% yield by the reaction of 4-methoxystyrene 2a with
10 mol % of the copper catalyst, 1 and p-TsOH in CH2Cl2 at 40 °C
(Scheme 3a). These reaction conditions also provided indole deriv-
ative 7n in 73% yield (Scheme 3b). Since compound 7a was ob-
tained by treatment of 4a with p-TsOH in 85% yield (Scheme 3c),
we supposed that this reaction would proceed via the oxytrifluo-
romethylated compound. It should be noted that these reactions
provided only the trans isomer. It is likely that the thermodynam-
ically favored trans isomer was formed through the E1 mechanism.
Similar b-trifluoromethylated styrene derivatives have been syn-
thesized by Wittig-type reaction or metal-catalyzed cross-coupling
reaction.4l,m,12 But, in general, these reactions require harsh reac-
tion conditions, and/or the stereoselectivity of products may be
problematic. Our catalytic transformation provides a new alterna-
tive for the synthesis of b-trifluoromethylstyrene derivatives.
Inspired by the above oxytrifluoromethylation of styrene deriva-
tives, we next examined alkynes as substrates. Recent reports of oxi-
dative trifluoromethylation of terminal alkyne have been focused on
the synthesis of trifluoromethylated acetylene derivatives13 and there
have been few descriptions of oxytrifluoromethylation.9,14 The reac-
tions of alkynes were much slower than those of alkenes. But,
although larger amounts of copper catalyst (30 mol %) and 1 were
needed, the corresponding products were obtained under mild condi-
tions (40 °C) in high yields (Eq. 3). In order to determine the stereo-
ð2Þ
Fortunately, we found that the reaction of 4-methoxystyrene 2a
in CH2Cl2 using CuI provided the desired oxytrifluoromethylation
product 4a in 86% yield (Table 1, entry 1). CuCl, CuTc, and CuOAc
were also good catalysts for the reaction (entries 2–4). Surpris-
ingly, the more Lewis acidic Cu(I) species gave 4a in high yield
within 5 min (entries 5, 6). Compound 4a was obtained in 94%
yield within 30 min by using [(MeCN)4Cu]PF6 as a catalyst, even
at 23 °C (entry 8). Cu(II) species also catalyzed this reaction, albeit
with moderate yield.
With optimized conditions in hand, the scope of the reaction
was next examined, as shown in Table 2. Oxytrifluoromethylation
Table 1
Optimization of reaction conditionsa
Entry
Cat.
Time
Yieldb [%]
1
2
3
4
5
6
7
8
9
CuI
CuCl
CuTc
CuOAc
CuOTfꢀtoluene
[(MeCN)4Cu]PF6
CuOTfꢀtoluenec
[(MeCN)4Cu]PF6
Cu(OTf)2
9 h
86
86
86
87
86
90
90
94
64
24 h
24 h
9 h
5 min
5 min
5 h
c
30 min
24 h
a
The reactions were carried out with catalyst (10 mol %) and Togni reagent 1
(1.2 equiv) in CH2Cl2 at 40 °C on a 0.2 mmol scale, unless otherwise mentioned.
b
Isolated yield.
Run at 23 °C.
c
Scheme 2. Further transformation of oxytrifluoromethylated compounds.

H. Egami et al. / Tetrahedron Letters 53 (2012) 5503–5506
5505
Table 2
Oxytrifluoromethylation of styrene derivativesa
Ar2
[(MeCN)4Cu]PF6 (10 mol%)
1
(1.2 equiv.)
O
O
Ar1
CF3
Ar1
CH2Cl2, 23 °C
4: Ar2 = 2-iodophenyl
2
Ar2
Ar2
Ar2
Ar2
O
O
O
O
O
O
O
O
CF3
CF3 MeO
CF3
Br
CF3
O
O
TBSO
HO
MeO
c
4c: 95% (30 min)
4d
: 81% (1 h)
4b: 88% (5 min)
4e: 85% (2 h)d
92% (5 min)b
Ar2
Ar2
Ar2
Ar2
O
O
O
O
O
O
O
O
CF3
CF3
CF3
CF3
OMe
OH
AcHN
4h
BocHN
4f
4g
4i
: 86% (12 h)
Ar2
: 80% (30 min)
Ar2
: 94% (5 min)
Ar2
: 93% (5 min)
Ar2
O
O
O
O
O
O
O
O
CF3
CF3
CF3
CF3
S
O
t-Bu
Br
4m
4j: 70% (12 h)d, e
4k
4l
: 63% (4 h)
: 67% (5 min)
: 74% (10 min)
Ar2
Ar2
Ar2
Ar2
O
O
O
O
O
O
Ph
O
O
CF3
CF3
CF3
CF3
Ph
Ph
AcN
4n
BocN
4o
g
e, f
: 86% (1 h)
: 67% (3 h)
4q
: 97% (2 h)
4p
: 91% (2 h)
a
b
c
d
e
f
The reactions were carried out with [(MeCN)4Cu]PF6 (10 mol %) and Togni reagent 1 (1.2 equiv) in CH2Cl2 at 23 °C on a 0.2 mmol scale, unless otherwise mentioned.
Run on a 2 mmol scale.
Run at 0 °C.
Run with 20 mol % of catalyst.
Run at 40 °C.
Run with CuI (10 mol %) as the catalyst.
Run on a 1 mmol scale.
g
chemistry of the products, we measured the NOESY spectra. No corre-
lation with the olefinic proton was observed. Thus, elimination of io-
dine atom was examined, because the product 10 has already been
reported (Eq. 4).14 Treatment of 9c with i-PrMgBr/LiCl15 and aqueous
NH4Cl provided 10 in 91% yield, and this result indicated that the ste-
reochemistry of the oxytrifluoromethylation products is trans.16
Cationic copper, [(MeCN)4Cu]PF6, worked as a catalyst for eth-
ynylbenzene derivatives, but the reaction efficiency of silylacety-
lene derivatives was low. This is because the decomposition of 1
to give trifluoromethyl-2-iodobenzoate17 was faster than the de-
sired reaction. Considering this phenomenon, we used CuI, which
did not catalyze the decomposition of Togni reagent under these
conditions, as the catalyst for silylacetylene derivatives. As a result,
the corresponding oxytrifluoromethylated products were obtained,
albeit in moderate yields (Eq. 5).
ð3Þ
ð4Þ

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H. Egami et al. / Tetrahedron Letters 53 (2012) 5503–5506
352, 2708–2732; (e) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470–
477; (f) Hollingworth, C.; Gouverneur, V. Chem. Commun. 2012, 48, 2929–2942.
3. For recent reviews on trifluoromethylation reactions, see: (a) Zheng, Y.; Ma, J.-
A. Adv. Synth. Catal. 2010, 352, 2745–2750; (b) Roy, S.; Gregg, B. T.; Gribble, G.
W.; Le, V.-D.; Roy, S. Tetrahedron 2011, 67, 2161–2195; (c) Tomashenko, O. A.;
Grushin, V. V. Chem. Rev. 2011, 111, 4475–4521; (d) Amii, H. J. Synth. Org. Chem.
Jpn. 2011, 69, 752–762; (e) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Asia J.
2012, 7, 1744–1754.
4. For selected reports on catalytic Csp2–CF3 bond-forming reactions, see: (a)
Oishi, M.; Kondo, H.; Amii, H. Chem. Commun. 2009, 1909–1911; (b) Wang, X.;
Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3648–3649; (c) Cho, E. J.;
Cenecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.; Buchwald, S. L. Science 2010,
328, 1679–1681; (d) Shimizu, R.; Egami, H.; Nagi, T.; Chae, J.; Hamashima, Y.;
Sodeoka, M. Tetrahedron Lett. 2010, 51, 5947–5949; (e) Wiehn, M. S.;
Vinogradova, E. V.; Togni, A. J. Fluorine Chem. 2010, 131, 951–957; (f)
Knauber, T.; Arikan, F.; Röschenthaler, G.-V.; Gooßen, L. J. Chem. Eur. J. 2011,
17, 2689–2697; (g) Xu, J.; Luo, D.-F.; Xiao, B.; Liu, Z.-J.; Gong, T.-J.; Fu, Y.; Liu, L.
Chem. Commun. 2011, 47, 4300–4302; (h) Liu, T.; Shen, Q. Org. Lett. 2011, 13,
2342–2345; (i) Mu, X.; Chen, S.; Zhen, X.; Liu, G. Chem. Eur. J. 2011, 17, 6039–
6042; (j) Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224–228; (k)
Parsons, A. T.; Senecal, T. D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2012, 51,
2947–2950; (l) He, Z.; Luo, T.; Hu, M.; Cao, Y.; Hu, J. Angew. Chem., Int. Ed. 2012,
51, 3944–3947; (m) Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2012, 134, 1298–1304;
(n) Ye, Y.; Sanford, M. S. J. Am. Chem. Soc. 2012, 134, 9034–9037.
5. For selected reports, see: (a) Umemoto, T.; Adachi, K. J. Org. Chem. 1994, 59,
5692; (b) Itoh, Y.; Mikami, K. Tetrahedron 2006, 62, 7199; (c) Nagao, H.; Yamane,
Y.; Mukaiyama, T. Chem. Lett. 2007, 36, 666; (d) Mizuta, S.; Shibata, N.; Akiti, S.;
Fujimoto, H.; Nakamura, S.; Toru, T. Org. Lett. 2007, 9, 3707; (e) Nagib, D. A.;
Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 10875; (f) Allen, A.
E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 4986; (g) Pham, P. V.; Nagib,
D. A.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2011, 50, 6119; (h) Deng, Q.-H.;
Wadepohl, H.; Gade, L. H. J. Am. Chem. Soc. 2012, 134, 10769–10772.
6. (a) Parsons, A. T.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 9120–9123;
(b) Xu, J.; Fu, Y.; Luo, D.-F.; Jiang, Y.-Y.; Xiao, B.; Liu, Z.-J.; Gong, T.-J.; Liu, L. J.
Am. Chem. Soc. 2011, 133, 15300–15303; (c) Wang, X.; Ye, T.; Zhang, S.; Feng, J.;
Xu, Y.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, 133, 16410–16413; (d) Mu, X.;
Wu, T.; Wang, H.-Y.; Guo, Y.-L.; Liu, G. J. Am. Chem. Soc. 2012, 134, 878–881; (e)
Chu, L.; Qing, F.-L. Org. Lett. 2012, 14, 2106–2109.
Scheme 3. Direct formation of trifluoromethylstyrenes.
ð5Þ
7. Recently, similar type reaction was reported, see: (a) Shimizu, R.; Egami, H.;
Hamashima, Y.; Sodeoka, M. Angew. Chem., Int. Ed. 2012, 51, 4577; (b) Mizuta,
S.; Galicia-López, O.; Engle, K. M.; Verhoog, S.; Wheelhouse, K.; Rassias, G.;
Gouverneur, V. Chem. Eur. J. 2012, 18, 8583–8587.
8. For selected reports on the trifluoromethylation using Togni reagent, see: (a)
Eisenberger, P.; Gischig, S.; Togni, A. Chem. Eur. J. 2006, 12, 2579–2586; (b)
Kieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chem., Int. Ed. 2007, 46, 754–757;
(c) Koller, R.; Stanek, K.; Stolz, D.; Aardoom, R.; Niedermann, K.; Togni, A.
Angew. Chem., Int. Ed. 2009, 48, 4332–4336; (d) Niedermann, K.; Früh, N.;
Vinogradova, E.; Wiehn, M. S.; Moreno, A.; Togni, A. Angew. Chem., Int. Ed. 2011,
50, 1059–1063.
9. Electrochemical and radical oxytrifluoromethylations of C@C bond were
reported, see: (a) Sato, Y.; Watanabe, S.; Uneyama, K. Bull. Chem. Soc. J. 1993,
66, 1840–1843; (b) Yajima, T.; Nagano, H.; Saito, C. Tetrahedron Lett. 2003, 44,
7027–7029; (c) Zhang, C.-P.; Wang, Z.-L.; Chen, Q.-Y.; Zhang, C.-T.; Gu, Y.-C.;
Xiao, J.-C. Chem. Commun. 2011, 47, 6632–6634.
In summary, copper-catalyzed oxytrifluoromethylation reaction
of styrene derivatives was achieved with high efficiency. In the
course of preparation of this Letter, a similar type of oxytrifluorom-
ethylation was reported by Szabó et al.10 but the reaction condi-
tions described here are much milder and faster than the
reported ones. The reaction products were further transformed
into
a-oxy-b-trifluoromethylated carbonyl compounds, which are
useful building blocks for potential drug candidate molecules.
Acknowledgments
10. Janson, P. G.; Ghoneim, I.; IIchenko, N. O.; Szabó, K. J. Org. Lett. 2012, 14, 2882–
2885.
11. The reaction of simple styrene is not clean and the yield of the desired
oxytrifluoromethylation product was only 29%.
This research was supported in part by a Grant-in-aid for Young
Scientists (B) from MEXT (23750116) and by Funding from RIKEN.
12. For selected reports on synthesis of b-trifluoromethylstyrene derivatives, see:
(a) Fuchikami, T.; Yatabe, M.; Ojima, I. Synthesis 1981, 365–366; (b) Kitazume,
T.; Ishikawa, N. J. Am. Chem. Soc. 1985, 107, 5186–5191; (c) Kobayashi, T.; Eda,
T.; Tamura, O.; Ishibashi, H. J. Org. Chem. 2002, 67, 3156–3159; (d) Hanamoto,
T.; Morita, N.; Shindo, K. Eur. J. Org. Chem. 2003, 4279–4285; (e) Prakash, G. K.
S.; Krishnan, H. S.; Jog, P. V.; Iyer, A. P.; Olah, G. A. Org. Lett. 2012, 14, 1146–
1149; (f) Omote, M.; Tanaka, M.; Ikeda, A.; Nomura, S.; Tarui, A.; Sato, K.; Ando,
A. Org. Lett. 2012, 14, 2286–2289.
13. (a) Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2010, 132, 7262–7263; (b) Zhang, K.;
Qiu, X.-L.; Huang, Y.; Qing, F.-L. Eur. J. Org. Chem. 2012, 58–61; (c) Luo, D.-F.; Xu,
J.; Fu, Y.; Guo, Q.-X. Tetrahedron Lett. 2012, 53, 2769–2772; (d) Weng, Z.; Li, H.;
He, W.; Yao, L.-F.; Tan, J.; Chen, J.; Yuan, Y.; Huang, K.-W. Tetrahedron 2012, 68,
2527–2531.
14. Another methodology for synthesis of such products was reported, see:
Kawatsura, M.; Namioka, J.; Kajita, K.; Yamamoto, M.; Tsuji, H.; Itoh, T. Org. Lett.
2011, 13, 3285–3287.
15. Krasovskiy, D.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333–3336.
16. This result suggests that this reaction proceeds via trans-addition of Togni
reagent, but further studies would be required to discuss the reaction
mechanism.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.07.134.
References and notes
1. (a)Modern Fluoroorganic Chemistry; Krisch, P., Ed.; Wiley-VHC: Weinheim,
2004; (b)Bioorganic and Medicinal Chemistry of Fluorine; Bégué, J.-P., Bonnet-
Delpon, D., Eds.; Wiley-VHC: Hoboken, 2008; (c)Fluorine in Medicinal Chemistry
and Chemical Biology; Ojima, I., Ed.; Wiley-Blackwell: Chichester, 2009; (d)
Jeschke, P. ChemBioChem 2004, 5, 570–589; (e) Shimizu, M.; Hiyama, T. Angew.
Chem., Int. Ed. 2005, 44, 214–231; (f) Schlosser, M. Angew. Chem., Int. Ed. 2006,
45, 5432–5446; (g) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–
1886; (h) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359–4369.
2. For selected recent reviews on fluorination reactions, see: (a) Hamashima, Y.;
Sodeoka, M. Synlett 2006, 1467–1478; (b) Ma, J.-A.; Cahard, D. Chem. Rev. 2008,
108, PR1–PR43; (c) Ueda, M.; Kano, T.; Maruoka, K. Org. Biomol. Chem. 2009, 7,
2005–2012; (d) Lectard, S.; Hamashima, Y.; Sodeoka, M. Adv. Synth. Catal. 2010,
17. Fantasia, S.; Welch, J. M.; Togni, A. J. Org. Chem. 2010, 75, 1779–1782.